This application is to support the development of Dr. Alix Ashare into an independent researcher and an accomplished clinician-scientist. Dr. Gary Hunninghake will assume the responsibility as mentor to ensure the success of the Career Development Plan. Dr. Ashare is currently enrolled in courses toward a Ph.D. in Translational Biomedicine. She has completed didactic training in study design, statistical methods, and graduate immunology. Specific areas of career development during this award will include further course work in immunology, microbiology, and cell biology, as well as regular educational interactions with her Ph.D. Thesis Committee. The proposed research investigates the mechanism and significance of Kupffer cell apoptosis during Pseudomonas sepsis. The liver is an important organ in sepsis because it plays a role in bacterial clearance and cytokine production. In Aim 1, Dr. Ashare will investigate the effect of Pseudomonas sepsis on hepatic bacterial clearance and Kupffer cell survival in a murine model. In addition to the primary infection, secondary infections occur during the course of sepsis. In Aim 2, Dr. Ashare will evaluate the role of secondary infection due to bacterial translocation of enteric organisms in the setting of sepsis-induced Kupffer cell apoptosis. In particular, Dr. Ashare will investigate the relationship between bacterial translocation and the development of multiple organ dysfunction syndrome (MODS) in the setting of impaired hepatic bacterial clearance. Aim 3 will be directed at investigating the mechanism of Kupffer cell apoptosis during Pseudomonas sepsis. Specifically, Dr. Ashare will investigate the role of tumor necrosis factor alpha and apoptosis signal-regulating kinase 1 in the induction of Kupffer cell apoptosis. Throughout Dr. Ashare's career development, she will interface with experts in immunology, microbiology, hepatology, biostatistics and study design, and pulmonary and critical care medicine. This intellectually rich environment will help foster her career development, providing ample opportunity for critical review throughout the period of this award. Both the mentor and the institution are highly committed to Dr. Ashare's scientific development and academic success. Dr. Ashare's proposed Research Plan has great clinical significance. Sepsis and MODS are associated with high mortality and a heavy cost burden. This Research Plan could provide insight into the pathophysiology of MODS in sepsis and provide direction for future therapeutic trials.